An effective CD8+ T cell response is critical for protection from intracellular infectious agents and tumor cells. Unfortunately, the molecular mechanisms of CD8+ T cell effector and memory establishment are unclear, preventing the development of effective vaccines and immunotherapeutics directed against many infectious threats and cancers. As a post-doctoral fellow in Dr. Reiner's laboratory, I have helped to demonstrate that mice with T cells lacking the two highly homologous T-box transcription factors, Eomesodermin (Eomes) and T-bet, develop an inappropriate effector CD8+ T cell response to acute infection with lymphocytic choriomeningitis virus (LCMV), fail to clear the infection, and die from inappropriate CD8+ T cell interleukin-17 secretion. Further work from Dr. Reiner's laboratory and my preliminary data demonstrate preferential effector differentiation in CD8+ T cells lacking Eomes and memory differentiation in CD8+ T cells lacking T-bet in the context of LCMV infection. These data lead to the hypothesis that the differentiation of CD8+ T cells into effector and memory compartments during an immune response is determined by the relative expression of T-bet and Eomes. In the project proposed, I will test this model of CD8+ T cell differentiation in two different types of immune challenges and will also investigate the transcriptional targets by which Eomes promotes the development of CD8+ T cell memory. In the first aim, CD8+ T cell effector and memory differentiation will be assessed in mice lacking T-bet, Eomes, or both, after infection with listeria monocytogenes, a bacterial pathogen. In the second aim, I will assess effector and memory CD8+ T cell differentiation during an anti-cancer immune response in mice lacking T- bet, Eomes, or both. In the third aim, I will combine a candidate target approach with an unbiased approach to determine the transcriptional targets of Eomes that are important in memory CD8+ T cell differentiation. The proposed work will help define the transcriptional regulatory mechanisms that underlie T cell differentiation over the course of an immune response and may provide key insights into how to clinically manipulate T cells to maximize their therapeutic potential. Through these studies I will gain the expertise required to be an independent investigator in tumor immunology and cellular therapy.